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Safety & Efficacy of NV1020 in Colorectal Cancer Metastatic to the Liver

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ClinicalTrials.gov Identifier: NCT00149396
Recruitment Status : Completed
First Posted : September 8, 2005
Results First Posted : April 24, 2018
Last Update Posted : April 24, 2018
Sponsor:
Information provided by (Responsible Party):
MediGene

September 6, 2005
September 8, 2005
December 29, 2015
April 24, 2018
April 24, 2018
July 2004
October 2008   (Final data collection date for primary outcome measure)
  • Incidence of Adverse Events and Dose Limiting Adverse Events [ Time Frame: From start of treatment through 12 months after completion of treatment ]
    Incidence of adverse events for all patients (N=32); Overall incidence ≥20%; Adverse events listed by Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term
  • NV1020 Pharmacokinetics - Presence of NV1020 in Body Fluids/Skin [ Time Frame: Daily for 2 weeks after the first and last NV1020 infusions ]
    Number of patients with NV1020 detected in saliva, skin, and/or mucosal surfaces; Analysis by polymerase chain reaction (PCR)
  • Clinical Laboratory Safety - Hematology [ Time Frame: Screening; after each NV1020 infusion; +7h, +24h, and +72h after NV1020 infusion; each chemotherapy visit; +3d, +7d, +14d after each chemo visit; 1 week after end of treatment ]
    Number of patients with clinically significant hematology laboratory abnormalities by NV1020 dose cohort (Post baseline)
  • Clinical Laboratory Safety - Chemistry [ Time Frame: Screening; after each NV1020 infusion; +7h, +24h, and +72h after NV1020 infusion; each chemotherapy visit; +3d, +7d, +14d after each chemo visit; 1 week after end of treatment ]
    Number of patients with post-baseline clinically significant laboratory chemistry abnormalities by NV1020 dose cohort
  • Clinical Laboratory Safety - Coagulation [ Time Frame: Screening; after each NV1020 infusion; +7h, +24h, and +72h after NV1020 infusion; each chemotherapy visit; +3d, +7d, +14d after each chemo visit; 1 week after end of treatment ]
    Number of patients with post-baseline clinically significant laboratory coagulation abnormalities by NV1020 dose cohort
  • Incidence of Adverse Events and Dose Limiting Adverse Events
  • Clinical laboratory safety results
  • NV1020 pharmacokinetics-presence of NV1020 in body fluids/skin
Complete list of historical versions of study NCT00149396 on ClinicalTrials.gov Archive Site
  • Mean Change From Baseline in Serum Carcinoembryonic Antigen (CEA) After Administration of NV1020 and 2 Cycles of Chemotherapy [ Time Frame: Screening (baseline), Chemo visit 1, Chemo visit 2, Follow-up Visit 1 (1 week after end of treatment), Follow-up Visit 2 (+6M), Follow-up Visit 3 (+9M), Follow-up Visit 4 (+12M) ]
  • Liver Tumor Response After Administration of NV1020 Followed by Chemotherapy, Determined by Radiological (Computed Tomography [CT] Scan) Assessment [ Time Frame: Screening (baseline), Chemo visit 1, Follow-up visits 1 (1 week post end of treatment), 2 (+6M), 3 (+9M), 4 (+12M) ]
    Maximum percentage changes in tumor diameter after administration of NV1020 followed by chemotherapy as measured by CT scan and Modified Response Evaluation Criteria in Solid Tumors (RECIST) assessment
  • Pharmacodynamic Effects of NV1020: NV1020 Neutralizing Antibody Titer Assay [ Time Frame: Screening, Chemo Visit 1, Follow-up Visits 1 (1 week post end of treatment), 2 (+6M), 3 (+9M), 4 (+12M) ]
    Mean change from baseline in NV1020 neutralizing antibody titer by dose cohort
  • Time to Disease Progression; Survival Time [ Time Frame: Progression: Chemo visit 1, FU1 (1 week post treatment), FU2 (+6M), FU3 (+9M), FU4 (+12M); Survival: death of patient ]
    Progression assessed from CT and PET measurements and is determined as an increase of greater than or equal to 25% in the sum of the products of perpendicular diameters of all tumors, or the appearance of any new lesion.
  • Pharmacodynamic Effects of NV1020: Serum Cytokines (INF Gamma) [ Time Frame: Baseline, after each NV1020 infusion (Visit 1, Visit 3, Visit 5, Visit 7) ]
    Median change from baseline of Interferon (INF) gamma 8 hours post NV1020 infusion (Visits 1, 3, 5, 7)
  • Pharmacodynamic Effects of NV1020: Serum Cytokines (IL-6) [ Time Frame: Baseline, after each NV1020 infusion (Visit 1, Visit 3, Visit 5, Visit 7) ]
    Median change from baseline of Interleukin-6 (IL-6) 8 hours post NV1020 infusion (Visits 1, 3, 5, 7)
  • Pharmacodynamic Effects of NV1020: Serum Cytokines (TNF-alpha) [ Time Frame: Baseline, after each NV1020 infusion (Visit 1, Visit 3, Visit 5, Visit 7) ]
    Median change from baseline of tumor necrosis factor (TNF-alpha) 8 hours post NV1020 infusion (Visits 1, 3, 5, 7)
  • Tumor response after administration of NV1020 followed by a minimum of 2 cycles of chemotherapy, determined by radiological (CT scan) assessment of liver size and PET scan
  • Mean change from baseline in serum CEA after administration of NV1020 and 2 cycles of chemotherapy
  • Pharmacodynamic effects of NV1020 (NV1020 neutralizing antibody titer assay, cytokines, CEA)
  • Time to Disease Progression; Survival Time
Not Provided
Not Provided
 
Safety & Efficacy of NV1020 in Colorectal Cancer Metastatic to the Liver
A Phase I/II, Open-label Study to Evaluate the Safety and Anti-tumor Effects of NV1020 Administered Repeatedly Via Hepatic Artery Infusion Prior to Second-line Chemotherapy, in Patients With Colorectal Adenocarcinoma Metastatic to the Liver

This study is an open-label study. It has two stages. Stage 1 is a dose escalation phase of the study to determine and evaluate the safety and tolerability of repeated treatments with a genetically engineered herpes simplex virus NV1020 administered locoregionally to the liver.

Stage 2 is to evaluate the dose found in Stage 1 to be "optimally tolerated". Stage 2 is to assess the efficacy of the optimally tolerated dose of NV1020 by itself and in combination with second-line chemotherapy.

Assignment to Stage 1 or Stage 2 of the study is determined by when the patient enters the study.

This study is designed to evaluate the effects of repeated treatments with NV1020, prior to second-line chemotherapy, and to determine an appropriate dose level of NV1020 in a multiple dose regimen for later Phase II studies.

Sequential, open-label cohort dose escalation of NV1020 (stage 1) followed by an expansion of one selected dose cohort (stage 2).

Study results will be reviewed periodically by an independent DSMB who will approve each cohort dose escalation.

During the dose escalation stage, 3 cohorts of patients (3 in each) will be treated with 4 fixed doses of NV1020, with the dose level increasing for successive cohorts. A patient will be observed for a minimum of 7 days after the first NV1020 infusion before the next patient in the same cohort is given NV1020. The first patient in the next higher dose cohort will receive NV1020 no earlier than 14 days after the last patient in the prior cohort has finished NV1020 infusions. One additional cohort (half log higher increment) may be approved by the DSMB, if considered necessary to define MTD. Dose-limiting toxicity will be determined using NCI CTC criteria and a suitable dose level for later evaluation will be selected.

In the second stage of the study, the dose cohort considered to show the best therapeutic index will be expanded by the addition of 18 further patients. For all patients in this study, investigational treatment with NV1020 will be followed by a minimum of two cycles of second-line therapy using anti-neoplastic drugs approved by the FDA for colorectal cancer and selected by the investigator.

All patients will be followed up periodically until death. Permission for autopsy will be sought.

Interventional
Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Colorectal Cancer
  • Liver Neoplasms
Drug: NV1020
NV1020 dose levels: 3x10^6, 1x10^7, 3x10^7, and 1x10^8 plaque forming units, administered via hepatic artery infusion, over 10 minutes and repeated every 1-2 weeks for 4-8 weeks
Experimental: Safety and antitumor effects of NV1020

Stage 1: Four escalating dose cohorts of NV1020 3x10^6 pfu, 1x10^7 pfu, 3x10^7 pfu, and 1x10^8 pfu administered via hepatic artery infusion, over 10 minutes and repeated every 1-2 weeks for 4-8 weeks followed by 2 cycles of chemotherapy.

Stage 2: Expansion of one dose cohort from Stage 1 of optimal NV1020 dose administered via hepatic artery infusion, over 10 minutes and repeated every 1-2 weeks for 4-8 weeks followed by 2 cycles of chemotherapy.

Intervention: Drug: NV1020
Sze DY, Iagaru AH, Gambhir SS, De Haan HA, Reid TR. Response to intra-arterial oncolytic virotherapy with the herpes virus NV1020 evaluated by [18F]fluorodeoxyglucose positron emission tomography and computed tomography. Hum Gene Ther. 2012 Jan;23(1):91-7. doi: 10.1089/hum.2011.141. Epub 2011 Oct 14.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
32
27
December 2008
October 2008   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  1. Ability to understand and willingness to sign a written informed consent (includes willingness to avoid physical intimacy during and for 2 weeks post NV1020 treatment)
  2. 18 years or more of age
  3. Colorectal adenocarcinoma histologically confirmed within one year prior to enrollment in the study
  4. Liver dominant metastases (CT-measurable lesions with less than 50% total liver involvement), histologically confirmed
  5. Failed conventional chemotherapy for metastatic disease (e.g. tumors no longer responding to 5-FU/leucovorin in combination with irinotecan or oxaliplatin with or without one monoclonal antibody)
  6. Candidate for additional chemotherapy (and/or experimental anti-cancer therapy, if this is the only remaining treatment option)
  7. Karnofsky Performance Status 70% or greater
  8. Life expectancy greater than or equal to 4 months, based on the investigator's opinion
  9. Seropositive for herpes simplex virus-1 (HSV-1)
  10. Fecund females: negative for pregnancy test (urine or serum)
  11. Effective double-barrier contraception for a minimum of 2 months following final infusion of NV1020

Exclusion Criteria:

  1. Dominant extrahepatic disease, including cerebral metastases, significant malignant ascites or other extrahepatic metastases that are symptomatic, in critical locations or otherwise likely to confound NV1020 evaluations, in the opinion of the investigator
  2. Seronegative for HSV-1
  3. Significant active/unstable non-malignant disease or laboratory test (hematology and chemistry) results that meet any of the following:

    • White blood cell count (WBC) less than or equal to 3 x 10e3/mm3
    • Absolute neutrophil count (ANC) less than or equal to 1.5 x 10e3/mm3
    • Platelets less than or equal to 100,000/mm3
    • Hemoglobin (Hgb) less than or equal to 9.0 g/dL
    • Prothrombin time/partial thromboplastin time (PT/PTT) > upper limit of normal (ULN)
    • Serum creatinine > 2.0 mg/dL
    • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times ULN or total bilirubin > 1.5 times ULN
    • Alkaline phosphatase > 2.5 times ULN
  4. Chemotherapy < 4 weeks prior to the first NV1020 infusion (mitomycin or nitrosurea < 6 weeks)
  5. Immunotherapy < 6 weeks prior to the first NV1020 infusion
  6. Radiotherapy (external or internal) to the liver
  7. Major surgery (excluding pump placement and cholecystectomy) ≤ 2 weeks prior to the first NV1020 infusion but the subject must be clinically stable. Pump placement and cholecystectomy ≤ 1 week prior to the first NV1020 infusion but the subject must be clinically stable
  8. Female who is pregnant or nursing
  9. Patients wishing to conceive within 2 months after the last infusion of NV1020
  10. Any investigational agent administered less than or equal to 4 weeks prior to NV1020 infusion
  11. Acute HSV infection requiring systemic antiviral therapy or history of serious HSV infection (e.g., ocular, encephalitic, etc.)
  12. Active viral hepatitis (evidence for infection with hepatitis A, B or C viruses)
  13. Known infection with HIV
  14. Known hypersensitivity to any component of the NV1020 formulation
  15. History of, or current, bleeding or coagulation disorder
  16. History of significant hepatic fibrosis, cirrhosis, or hemachromatosis
  17. History of malignancy other than colorectal cancer, within 5 years prior to start of study participation, with the exception of in situ cervical or skin carcinoma
  18. Active severe infection and any other concurrent disease or medical conditions that are likely to interfere with the study, as judged by the investigator
  19. Systemic corticosteroid administration < 4 weeks prior to starting NV1020 treatment
  20. Prior treatment with NV1020 or other putative oncolytic viruses
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00149396
CT1030
Yes
Not Provided
Plan to Share IPD: No
MediGene
MediGene
Not Provided
Study Director: Hoda Tawfik, PhD MediGene
MediGene
March 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP